Enhanced conjugation stability and blood circulation time of macromolecular gadolinium-DTPA contrast agent

In this study, we prepared macromolecular MR T1 contrast agent: pullulan-conjugated Gd diethylene triamine pentaacetate (Gd-DTPA-Pullulan) and estimated residual free Gd^{3 +}, chelation stability in competition with metal ions, plasma and tissue pharmacokinetics, and abdominal MR contrast on rats. Residual free Gd^{3 +} in Gd-DTPA-Pullulan was measured using colorimetric spectroscopy. The transmetalation of Gd^{3 +} incubated with Ca^{2 +} was performed by using a dialysis membrane (MWCO 100-500 Da) and investigated by ICP-OES. The plasma concentration profiles of Gd-DTPA-Pullulan were estimated after intravenous injection at a dose 0.1 mmol/kg of Gd. The coronal-plane abdominal images of normal rats were observed by MR imaging. The content of free Gd^{3 +}, the toxic residual form, was less than 0.01%. Chelation stability of Gd-DTPA-Pullulan was estimated, and only 0.2% and 0.00045% of Gd^{3 +} were released from Gd-DTPA-Pullulan after 2 h incubation with Ca^{2 +} and Fe^{2 +}, respectively. Gd-DTPA-Pullulan displayed the extended plasma half-life (t_1/2,α = 0.43 h, t_1/2,β = 2.32 h), much longer than 0.11 h and 0.79 h of Gd-EOB-DTPA. Abdominal MR imaging showed Gd-DTPA-Pullulan maintained initial MR contrast for 30 min. The extended plasma half-life of Gd-DTPA-Pullulan probably allows the prolonged MR acquisition time in clinic with enhanced MR contrast.